Abstract 5075: Antitumor activity of liposomal formulation of eribulin combined with anti-human PD-1 antibody using hPBMC-humanized mouse models
Authors: Yuki Niwa, Taro Semba
Journal: Cancer Research (2023)

Abstract Eribulin (ERI) has been reported a microtubule dynamics inhibitor with unique tumor microenvironment modulations such as vascular remodeling and reversal of epithelial-mesenchymal transition activities. In the previous meeting (AACR2022), we reported that ERI and liposomal formulation of ERI (ERI-LF) have immunomodulatory activity that induces CD8+ T cells via its vascular remodeling activity and ERI-LF has greater immunomodulatory activity than ERI. Furthermore, we also reported that these immunomodulatory activities contribute combination antitumor activity of ERI and ERI-LF with anti-PD-1 antibody (Ab) using a P-glycoprotein-knockout 4T1 mouse breast cancer syngeneic model; however, evaluation of antitumor activity of immune-checkpoint inhibitor (ICI) using mouse cancer syngeneic model has limitation because numbers and cancer types of mouse cancer cell lines are limited. In this study, we developed humanized mouse model bearing both human cancer cell lines and human peripheral blood mononuclear cells (hPBMC) to evaluate antitumor activity of ICI for various cancer types. Furthermore, we also evaluated combination antitumor activity of ERI-LF with anti-human PD-1 Ab using this hPBMC-humanized mouse models to verify generality of this combination. We first isolated hPBMC from healthy volunteers and the obtained hPBMC was intravenously injected into NOG mice. To confirm transplantation of hPBMC in the mice, we performed flow cytometric analysis of peripheral blood of mice in a time course manner. In the peripheral blood of humanized mice, chimera ratio of hCD45+ cells gradually increased until 5 weeks after hPBMC-injection and then decreased after 6 weeks after hPBMC-injection. Because tumor growth of some cancer cell lines was rejected by hPBMC transplantation, we evaluated some human cancer cell lines that are able to grow in hPBMC-humanized condition and selected MKN45 and NCI-H526 cell lines for human gastric cancer and small cell lung cancer models, respectively. Finally, we verified combination antitumor activity of ERI-LF with anti-human PD-1 Ab in hPBMC-humanized MKN45 and NCI-H526 models. In both models, combination of ERI-LF with anti-human PD-1 Ab showed significantly stronger antitumor activity compared with each monotherapy. In summary, we demonstrated that combination of ERI-LF with anti-PD-1 Ab is effective for gastric and small cell lung cancers, suggesting that this combination therapy is effective for various cancer types. Currently, Phase 1b/2 clinical trial of ERI-LF plus nivolumab in patients with selected solid cancers including gastric and small cell lung cancers (NCT04078295) is underway. Citation Format: Yuki Niwa, Taro Semba. Antitumor activity of liposomal formulation of eribulin combined with anti-human PD-1 antibody using hPBMC-humanized mouse models. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5075.